Hemiplegic Migraine Associated With PRRT2 Mutations: A Clinical and Genetic Study

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012947
Author(s):  
Florence Riant ◽  
Caroline Roos ◽  
Agathe Roubertie ◽  
Cécile Barbance ◽  
Jessica Hadjadj ◽  
...  
Keyword(s):  
Learning Disabilities ◽  
Dominant Gene ◽  
Clinical Manifestations ◽  
Familial Hemiplegic Migraine ◽  
Loss Of Function ◽  
Hemiplegic Migraine ◽  
Pathogenic Variants ◽  
Paroxysmal Kinesigenic Dyskinesia ◽  
Wide Range

Background and objective:PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.Methods:PRRT2 was analyzed in 860 probands with hemiplegic migraine and PRRT2 mutations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with mutations whose clinical manifestations were detailed.Results:PRRT2 mutations were found in 12 of 163 probands previously tested negative for CACNA1A, ATP1A2 and SCN1A mutations, and in 18 of 697 consecutive probands screened simultaneously on the four genes. In this second group, pathogenic variants were found in 105 subjects, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%) and SCN1A (15%). The PRRT2 mutations included seven distinct variants, five of which already described in persons with paroxysmal kinesigenic dyskinesia, and two new variants. Eight probands had a deletion of the whole PRRT2 gene.Among the 49 PRRT2 mutated patients, 26 had pure hemiplegic migraine, 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4) or abnormal movement (3). Three patients had epilepsy without migraine, two had paroxysmal kinesigenic dyskinesia without migraine, and one was asymptomatic.Conclusion:PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine, and screened in any affected patient, together with the three other main genes. Further studies are needed to understand how the same loss of function PRRT2 mutations can lead to a wide range of neurologic phenotypes including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder and hemiplegic migraine.

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

Trigger factors for familial hemiplegic migraine

Cephalalgia ◽  
2011 ◽  
Vol 31 (12) ◽  
pp. 1274-1281 ◽  
Author(s):  
Jakob Møller Hansen ◽  
Anne Werner Hauge ◽  
Messoud Ashina ◽  
Jes Olesen
Keyword(s):  
Migraine With Aura ◽  
Response Rate ◽  
Bright Light ◽  
Familial Hemiplegic Migraine ◽  
Population Based ◽  
Trigger Factor ◽  
Trigger Factors ◽  
Hemiplegic Migraine

Objective: The aim was to identify and describe migraine trigger factors in patients with familial hemiplegic migraine (FHM) from a population-based sample. Methods: 127 FHM patients were sent a questionnaire listing 16 trigger factors. Distinction was made between attacks of hemiplegic migraine (HM) and migraine with aura (MA) or without aura (MO) within each patient. Results: The response rate was 59% (75/127) of whom 57 (76%) had current HM attacks. Sixty-three per cent (47/75) reported at least one factor triggering HM, and 36% (27/75) reported at least one factor that often or always caused HM. Twenty per cent (15/75) reported only HM, whereas FHM in combinations with MA and MO were reported by 80% (60/75). Stress (with attacks either following or during the stress), bright light, intense emotional influences and sleeping too much or too little were the trigger factors mentioned by most. Conclusion: Many FHM patients report trigger factors and one-third reported at least one trigger factor often or always triggering FHM. The typical triggers are the same as for MA. Patients should be educated to avoid these factors. The role of trigger factors in the onset of new or first attacks of FHM remains unknown.

A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

Cephalalgia ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 1382-1395
Author(s):  
Wenjing Tang ◽  
Meichen Zhang ◽  
Enchao Qiu ◽  
Shanshan Kong ◽  
Yingji Li ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Pathogenic Mutation ◽  
Familial Hemiplegic Migraine ◽  
Chinese Family ◽  
Hemiplegic Migraine ◽  
Pathogenic Potential ◽  
The Family

Background ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation. Methods Clinical manifestations in the family were recorded. Blood samples from patients and the unaffected members were collected for whole-exome sequencing to identify the pathogenic mutation. Seven online softwares (SIFT, PolyPhen-2, PROVEAN, PANTHER, MutationTaster2, MutationAssessor and PMut) were used for predicting the pathogenic potential of the mutation. PredictProtein, Jpred 4 and PyMOL were used to analyze structural changes of the protein. The mutation function was further tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Results All patients in the family had typical hemiplegic migraine attacks. Co-segregation of the mutation with the migraine phenotype in four generations, with 10 patients, was completed. The identified novel mutation, G762S in ATP1A2, exhibited the disease-causing feature by all the predictive softwares. The mutation impaired the local structure of the protein and decreased cell viability. Conclusion G762S in ATP1A2 is a novel pathogenic mutation identified in a Chinese family with familial hemiplegic migraine, which causes loss of function by changing the protein structure of the Na+/K+-ATPase α2 subunit.

scholarly journals Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1648
Author(s):  
Daniel Liedtke ◽  
Christine Hofmann ◽  
Franz Jakob ◽  
Eva Klopocki ◽  
Stephanie Graser
Keyword(s):  
Alkaline Phosphatase ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Systemic Disease ◽  
Loss Of Function ◽  
Inorganic Pyrophosphate ◽  
Wide Range ◽  
Mineralization Processes ◽  
Tissue Nonspecific Alkaline Phosphatase

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

Differential effect of FHM2 mutation on synaptic plasticity in distinct hippocampal regions

Cephalalgia ◽  
2019 ◽  
Vol 39 (10) ◽  
pp. 1333-1338 ◽  
Author(s):  
Antonio de Iure ◽  
Petra Mazzocchetti ◽  
Guendalina Bastioli ◽  
Barbara Picconi ◽  
Cinzia Costa ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Familial Hemiplegic Migraine ◽  
Loss Of Function ◽  
Hemiplegic Migraine ◽  
Term Potentiation ◽  
Atp1a2 Gene ◽  
Ca1 Area ◽  
Reduced Rate

Introduction Familial hemiplegic migraine 2 is a pathology linked to mutation of the ATP1A2 gene producing loss of function of the α2 Na+/K+-ATPase (NKA). W887R/+ knock-in (KI) mice are used to model the familial hemiplegic migraine 2 condition and are characterized by 50% reduced NKA expression in the brain and reduced rate of K+ and glutamate clearance by astrocytes. These alterations might, in turn, produce synaptic changes in synaptic transmission and plasticity. Memory and learning deficits observed in familial hemiplegic migraine patients could be ascribed to a possible alteration of hippocampal neuronal plasticity and measuring possible changes of long-term potentiation in familial hemiplegic migraine 2 KI mice might provide insights to strengthen this link. Results Here we have investigated synaptic plasticity in distinct hippocampal regions in familial hemiplegic migraine 2 KI mice. We show that the dentate gyrus long-term potentiation of familial hemiplegic migraine 2 mice is abnormally increased in comparison with control animals. Conversely, in the CA1 area, KI and WT mice express long-term potentiation of similar amplitude. Conclusions The familial hemiplegic migraine 2 KI mice show region-dependent hippocampal plasticity abnormality, which might underlie some of the memory deficits observed in familial migraine.

Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications

2001 ◽  
Vol 3 (29) ◽  
pp. 1-10 ◽  
Author(s):  
Tahir Tellioglu ◽  
David Robertson
Keyword(s):  
Orthostatic Intolerance ◽  
Clinical Manifestations ◽  
Synaptic Cleft ◽  
Norepinephrine Transporter ◽  
Genetic Mutation ◽  
Clinical Syndrome ◽  
Loss Of Function ◽  
Direct Association ◽  
Type Gene

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome.

scholarly journals Allergic Rhinoconjunctivitis: the Role of Histamine

1994 ◽  
Vol 3 (3) ◽  
pp. 171-175 ◽  
Author(s):  
M. Andersson ◽  
L. Greiff ◽  
C. Svensson
Keyword(s):  
Clinical Practice ◽  
Allergic Reaction ◽  
Clinical Manifestations ◽  
Allergen Challenge ◽  
Allergic Rhinoconjunctivitis ◽  
Full Spectrum ◽  
First Line Therapy ◽  
Wide Range ◽  
Atopic Condition

Allergic rhinoconjunctivitis is the most common atopic condition encountered in clinical practice. Analysis of the pathogenesis of this condition permits identification of optimal therapeutic targets. The increased knowledge of the underlying pathophysiology suggests that multiple inflammatory mediators are involved in the pathogenesis of the allergic reaction in the ocular and nasal mucosa. However, despite the presence of a wide range of different mediators, it would appear that histamine plays a key role. Experimental allergen challenge studies have demonstrated that histamine is the only mediator which produces the full spectrum of clinical manifestations of the acute allergic reaction when applied to the mucosal surface. While both H1- and H2-receptors are present in the nasal and ocular mucosa, only H1-receptor antagonists are capable of inhibiting histamine-induced symptoms of allergic rhinoconjunctivitis. Furthermore, although the exact role of histamine in the immediate and prolonged allergic reaction has not yet been fully elucidated, these findings do not exclude the possibility that histamine is involved in these processes. The available evidence therefore supports current clinical practice for use of H1-receptor antagonist as a first-line therapy in patients with this atopic condition.

scholarly journals Diagnosis and theraphy of urinary infections. What should always remember (clinical lecture). Part 1

2017 ◽  
Vol 7 (3) ◽  
pp. 52-59
Author(s):  
Vladimir V Borisov
Keyword(s):  
Laboratory Data ◽  
Clinical Manifestations ◽  
Diagnostic Features ◽  
Important Place ◽  
Sexually Transmitted ◽  
Urinary Infections ◽  
Wide Range ◽  
Tract Infections ◽  
Clinical Lecture

The clinical lecture is devoted to the systematization of the knowledge of a wide range of physicians and urologists about the importance of the problem of uncomplicated urinary tract infections, their prevalence in our country and the world, the causes and frequency of occurrence in children and adults, diagnostic features based on clinical manifestations of the disease, laboratory data taking into account the formation of biofilms, the presence of sexually transmitted diseases. A special place is given to the problem of recurrences of cystitis due to the anatomical features of the female urethra, the need and the possibilities for their correction. An important place in the lecture is devoted to the role of general practitioners, district therapists, nephrologists, urologists, gynecologists in outpatient examination and treatment of these patients. (For citation: Borisov VV. Diagnosis and theraphy of urinary infections. What should always remember (clinical lecture). Part 1. Urologicheskie vedomosti. 2017;7(3):52-59. doi: 10.17816/uroved7352-59).

scholarly journals RIPK1-Associated Inborn Errors of Innate Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahui Zhang ◽  
Taijie Jin ◽  
Ivona Aksentijevich ◽  
Qing Zhou
Keyword(s):  
Immune Deficiency ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Physiological Role ◽  
Model Organisms ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
Cell Death Signaling

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.

scholarly journals Clinical Profile and Role of Septic Screen in Early Onset Sepsis in a Tertiary Care Hospital of Western Nepal - A Prospective Observational Study

2020 ◽  
Vol 8 (1) ◽  
pp. 14-18
Author(s):  
Binod Kumar Gupta ◽  
Raju Kaphle ◽  
Buby Philip Kurian ◽  
Badri Kumar Gupta
Keyword(s):  
Respiratory Distress ◽  
Neonatal Sepsis ◽  
Early Onset ◽  
Tertiary Care ◽  
Clinical Manifestations ◽  
Coagulase Negative Staphylococcus ◽  
Care Hospital ◽  
Early Onset Sepsis ◽  
Wide Range

INTRODUCTION: Neonatal sepsis is an important cause of neonatal mortality and morbidity with wide range of clinical manifestations. This study was aimed to study the clinical characteristics of sepsis along with the role of septic screen for early diagnosis of septicemia. MATERIAL AND METHODS: A prospective observational hospital based cross-sectional study was conducted in 113 screen positive newborns over a 12-month period at Universal College of Medical Sciences, Teaching Hospital Bhairahawa, Nepal. RESULTS: Out of 489 cases admitted to the NICU during the study period, 113 babies with screen positive sepsis were included in the study. Poor feeding (46%, n=52), respiratory distress (38.9%, n=44) and lethargy (30.1%, n=34) were top three clinical presentations in neonates with sepsis followed by seizures, jaundice, vomiting, fever and hypothermia respectively. 57.5% (n=65) of clinical sepsis cases enrolled had culture positivity with staphylococcus aureus in 41.5% (n=27) and Coagulase negative Staphylococcus (CONS) in 27.7% (n=18).  Klebsiella was the third common organism isolated in blood culture (23.1%, n=15). The sensitivities and specificities of two-test and three-test combinations in proven sepsis was calculated. Two-test combinations showed sensitivities between 33-100% and specificities between 30-90% whereas three-test combinations showed the sensitivities and specificities between 60-100% and 20-90% respectively. CONCLUSION: Poor feeding, respiratory distress and lethargy were common presentations in early onset neonatal sepsis. Three-test combination of septic screen had no overall advantage over two-test combination in the present study.

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